Genes and their associated enzymatic complexes govern the main pathways of autophagy. Macroautophagy is the pathway for removal of degraded or damaged proteins and organelles at a cellular level. Modulation of this highly specific process has been a general approach toward the treatment of diseases associated with cellular over-accumulation of some misfolded proteins. Whereas the other major protein clearance pathway, the ubiquitin proteasome pathway, is unable to degrade aggregated proteins (normal or misfolded), autophagy can engulf and clear protein aggregates as well as monomeric proteins. Misfolded proteins, as monomers or in aggregates, can cause neurodegeneration by using up critical components of the chaperone-protein folding processes and protein clearance pathways, leading to additional protein misfolding and the loss of function of a variety of essential proteins. Aggregates may also cause direct damage to organelles and interfere with an array of cellular functions such as transcription and axonal transport. Likewise, abberant autophagy is implicated in various cancers. Thus, compositions and methods which stimulate the autophagic clearance of misfolded proteins and/or protein aggregates is of considerable interest.
An illustrative example of neurodegenerative disorders related to cellular over-accumulation of misfolded proteins is Huntington's disease. Huntington's disease is categorized as a trinucleotide repeat disorder and caused by expansion of a repeated section of the gene, HTT, that encodes the protein HUNTINGTIN. Normal HUNTINGTIN protein contains a region referred to as the “PolyQ region”, which has a repeated sequence of the DNA triplet base cytosine-adenine-guanine (CAG), which codes for the amino acid glutamine (Q). A mutant HUNTINGTIN gene, mHTT, generates a mutant HUNTINGTIN protein with a PolyQ region containing greater than 36 glutamine residues. This mutant protein is misfolded and is also cleaved to produce numerous fragments. Both the misfolded protein and the fragments are contemplated to be particularly toxic. Accordingly, areas of the brain possessing cells with the mutant gene and correspondingly high likelihood and/or presence of misfolded protein are found to show a correspondingly higher incidence of adverse effects.
Another example of a misfolded-protein associated disorder is Parkinson's disease. In Parkinson's patients, over-expression of the protein, α-SYNUCLEIN, can result from duplication or triplication of the SNCA gene locus and occurs for unknown reasons in the vast majority of Parkinson's patients, who develop the disease without any identifiable mutation. In addition, A53T and A30P point mutations of the gene have been demonstrated to trigger the early onset of Parkinson's. Further, over-expression of the wild type protein in transgenic mice and flies has been shown to cause progressive neuronal defects. The accumulation of α-SYNUCLEIN in misfolded and aggregated forms, is strongly associated with neuronal dysfunction and death. Clearly, the homeostatic removal of misfolded proteins and/or protein aggregates is a prime therapeutic target for the treatment of Huntington's, Parkinson's, and other such related disorders.
Examples of other disorders and diseases categorized as proteopathies include, but are not limited to: Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia of types 1, 2, 3, 6, 7 and 17, spinobullar muscular atrophy; dentatorubral-palli-doluysian atrophy, peripheral neuropathy, and dementia. Treatment of these types of diseases can be affected by the administration of an active pharmaceutical ingredient, which is capable of inducing autophagic removal of the particular toxic misfolded proteins and/or protein aggregates.
Some bacterial and viral infections are treatable by autophagic upregulation, as well. Pathogens can be engulfed by autophagosomes and further disposed of by lysosomes. Streptococcus (Group A) and Herpes virus (Type I) are important examples of pathogens, although not limiting, that are susceptible to this kind of capture.
There remains a need for compounds that are effective stimulants of autophagic removal of misfolded proteins and/or protein aggregates and such compounds can be used in treating neurodegenerative disorders. Compounds that induce neuronal autophagy and can be used to treat and prevent neurodegenerative disorders characterized by misfolded proteins and/or protein aggregates are provided herein.